Synergistic antiseptic compositions containing a halogenated anilide of thiophene carboxylic acid

ABSTRACT

COMPOSTIONS POSSESSING ANTIBACTERIAL ACTIVITY THROUGH THE EFFECTS OF A SYNERGISTIC COMBINATION OF THIOPHENE-2-CARBOXY-4&#39;&#39;-BROMOANILIDE AND EITHER HEXACLOROPHENE OR TRIBROMOSALICYLANILIDE.

United States Patent 3,741,952 SYNERGISTIC ANTISEPTIC COMPOSITIONS CON- TAINING A HALOGENATED ANILIDE 0F THIO- PHENE CARBOXYLIC ACID David Taber, 2000 Lincoln, Evanston, Ill. 60433 No Drawing. Filed Mar. 8, 1971, Ser. No. 122,093

Int. Cl. Clld 3/48, 9/50 US. Cl. 252-407 1 Claim ABSTRACT OF THE DISCLOSURE Compositions possessing antibacterial activity through the effects of a synergistic combination of thiophene-Z-carboxy-4-bromoanilide and either hexaclorophene or tribromosalicylanilide.

In accordance with the present invention, it has been found that combinations of either hexachlorophene or tribromosalicylanilide with thiophene-Z-carboxy-4'-bromoanilide exhibit synergistic antibacterial activities, and that the synergistic activities are maintained unimpaired when such mixtures are incorporated into various cleansing compositions such as soap and other detergent and cosmetic preparations. The term synergistic activity as applied herein means an antibacterial effect which is greater in combination than the sum of the antibacterial effects of the separate components. The occurrence of synergistic activity is highly unexpected and unusual.

The present invention relates to antiseptic compositions which possess synergistic antibacterial activities through the effects of combinations of antibacterial agents. More specifically the present invention relates to combinations of either hexachlorophene or tribromosalicylanilide with a halogenated anilide of thiophene carboxylic acid, preferably thiophene-Z-carboxy-4-bromoanilide having the formula:

WTLMQAB.

Antiseptic or antibacterial agents have been used in soaps and other detergents and cosmetic cleansing preparations for a considerable period of time. One of the most widely used of such agents has been hexachlorophene [2,2-methylene-bis(3,4,6-trichlorophenol)], as described in Us. Pat. 2,535,077. The Bright US. Pat. 3,284,363 discloses antibacterial activity of halogenated salicylanilides such as tribromosalicylanilide (3,4',5-tribromosalicylanilide and its position isomers). The Stecker U.S.

Pats. 3,243,342 and 3,303,201, disclose antibacterial acice invention will become apparent from the ensuing description and examples.

In a specific embodiment, this invention may be exemplified by a soap composition containing as the antibacterial agent a synergistic mixture of (A) thiophene-2- carboxy-4'-bromoanilide and (B) either hexachlorophene or tribromosalicylanilide and wherein the ratio of A to B present in the soap in parts by weight is about one to one, although other ratios will be suitable to obtain synergistic results.

It is found that when components A and B of the synergistic mixture as set forth above are used together, a germicidal effect is achieved which is substantially greater than the mere total of the individual effects of the individual ingredients. Such effect is important in cases where it is desirable to increase the activity of any one of the individual antiseptic ingredients without employing higher concentrations of that ingredient. Such effect is also important in cases where it is desirable to reduce the total concentration of antibacterial agents while at the same time maintaining a desired level of antibacterial effect, or to reduce the incidents of drawbacks to the use of any one of the individual ingredients in the product while maintaining high antibacterial effectiveness. The present invention is still further important in that this synergistic phenomena occurs even at the high pH conditions existing in alkaline detergent formulations such as soap.

The term soap refers to the water-soluble ammonium, phosphorus, metallic, or organic base (such as alkyl or alkoxy-alkyl containing up to about 9 carbon atoms) salts of various natural or synthetic fats, oils, or fatty acids containing aliphatic radicals having from about 12 to 22 carbon atoms. Such aliphatic radicals may be principally dodecyl, tetradecyl, hexadecyl, octadecyl; and the fatty acids may be chiefly lauric, oleic, stearic and palmitic acids. -As used in this description, the term is intended to cover all products in which soap is a major constituent, for example bar, flake, powder, gel and liquid soap; shaving cream; toothpaste; facial and cleansing cream; and the like.

Further the soap ingredient may be partially substantially or completely replaced with anionic type and nonionic type synthetic detergents. The anionic type synthetics can be described as those detergents having pronounced cleansing power and including in their molecular structure an alkyl radical containing from 6 to 18 carbon atoms and a sulfonic acid or sulfuric acid ester radical. Either organic base, ammonium, sodium or potassium salts of such anionc type detergents can be used. Principal types of detergents falling within this category and suitable for use in the present invention are alkyl-aryl sulfonates such as sodium or potassium dodecyl benzene sulfonate, sodium or potassium octadecyl benzene sulfomate, and sodium or potassium octyl naphthalene sulfonate; the alkyl sulfates such as sodium or potassium salts of dodecyl, hexadecyl, and octadecyl sulfates; the sulfonated fatty acid amides such as sodium or potassium salts of the oleic acid amide of methyl taurine; and the sulfonated monoglycerides such as the mono-coconut oil fatty acid ester of sodium l,2-hydroxypropane-3-sulfonate.

The nonionic type synthetic detergents can be described as those detergents which do not ionize in solution but owe their water-solubility to un-ionized polar groups such as hydroxy, oxyethyl or ether linkages. Principal types of detergents falling within this category are illustrated by the polyoxyethylene ethers of the higher fatty alcohols and alkyl phenols; the polyethylene glycols of fatty acids; fatty alkylol amide condensation products; polymers of ethylene and propylene oxides; compounds formed by the addition of propylene oxide to ethylene diamine followed by addition of ethylene oxide; fatty acid-ethylene oxide condensation products; condensation products of ethylene oxide and a fatty acid ester of a polyhydric alcohol or sugar; and the detergents prepared by heating to gether a higher fatty acid with a diethanolamine. Exemplary of such synthetic nonionic detergents which are suitable for use in the present invention are ethylene oxidetall oil fatty acid reaction products; isooctyl phenol-ethylene oxide reaction products; propylene oxide-ethylene oxide reaction products; and combinations of isooctyl phenol-ethylene oxide with coconut oil or the like fatty acid ethylene oxide reaction products.

Relatively small amounts of the components of our synergistic mixtures are sufficient for the increased antibacterial eifects in the antiseptic product. Satisfactory results can be obtained when the combined weights of the above two components A and B are from about 0.1% to of the total weight of the detergent composition. A preferred range is a weight concentration of about 0.2% to 4%, and an especially preferred antiseptic product is one containing soap and about 1.5% to 3% combined weight of the above two components, by weight of the composition. It should be understood that concentrations below the ranges set forth above will provide some degree of synergistic antibacterial effects, and a substantially higher concentration than those referred to will also give satisfactory results, although there are economic and other practical considerations which limit the desirability of greater amounts.

The synergistic combinations of the thiophene-2-carboxy-4-bromoanilide and either hexachlorophene or tribromosalicylanilide can be added to the soap, detergent or other antiseptic product by any suitable method which results in a uniform distribution of the agents throughout the entire mass.

Specific examples illustrating this invention are set forth as follows:

EXAMPLE I A convenient and meaningful method of measuring the antibacterial effectiveness of various agents is by means of a modified agar streak method utilizing a soap solution (100,000 p.p.m. of soap) containing the various test agents. Briefly the test consists of making serial dilutions of the following solution: 10 ml. of a solution containing a specific quantity of the test agent(s) in dimethyl formamide is dispensed into 80 ml. of distilled water containing 10 grams of soap (or 90 ml. of distilled water if the agents are to be tested without the presence of soap). All solutions are maintained at 60 C. until they are dispensed. Aliquots of the dilutions containing concentrations of the bacteriostatic agents ranging from about 0.02 to 10 p.p.m. at 50 C. are thoroughly dispensed into measured amounts of nutrient agar. The agar is then poured into dishes, allowed to solidify, and streaked with a standard 4 mm. loopful of a 24-hour broth culture of either Staphylococcus aureus FDA 209 or Escherichia coli ATCC 11229. After incubation for 24-hours at 37 C. the bacteriostatic endpoint is determined. The bacteriostatic endpoint, hereinafter called the minimum inhibitory concentration (MIC), represents the minimum concentration in parts per million by weight of the bacteriostatic agent(s) necessary to inhibit all growth of the innoculent organism. No particular minimum inhibitory concentration has been established to determine the usefulness of a bacteriostatic agent, although the lower the endpoint, the better the bacteriostatic activity and the smaller the amount of the agent(s) necessary to maintain a particular degree of effectiveness. The soap utilized for these evaluations was a neutral white toilet soap containing about 20% by weight of sodium coco soap and 80% by weight of sodium tallow soap.

Using the modified agar streak method as set forth above, bacteriostatic effectiveness against S. aureus of a soap solution containing 1% of each of the test agents alone and 1% of 50/ 50 proportions was determined. The results are as follows:

MIC found (p.p.m.) versus S. aureus With Without Test agent (s) soap soap 1% thi0phene-?rearboxy-4-bromoanillde 10 10 1% hexachlorophene 0. 4 0. 3 1% tribromosalicylanilide 0.6 0. 5 0.5% thlophene-%earboxy-4-bromoa ide plus 0.5% hexachlorophene 0. 4 0. 4 0.5% thiophene-2-carboxy-4-bromoanillde plus 0.5% tribromosallcylanilide 0. 6 0. 9

EXAMPLE II Using the modified agar streak method set forth above, additional results illustrating the bacteriostatic effectiveness against E. coli were determined and are as follows:

MIC found (p.p.m.) versus E. coli The above results were obtained with same day evaluations to avoid day-to-day variations in bacteriological testing. When the greater than symbol was used, this meant that some trace colonies were observed at that concentration.

The results set forth in the foregoing examples with respect to a specific soap (20% sodium coco and sodium tallow soap) are obtained with soaps generally. Thus, the ratio of sodium coco to sodium tallow soap may vary from 45/55 to 10/90. Also, a fatty acid soap such as sodium laurate, potassium stearate, sodium oleate, and potassium myristate will produce these results. Furthermore, the synergistic action is independent of the soap medium and will take place in non-detergent media as well as in anionic detergents other than soap and in nonionic detergents systems. At the same time, soap is a system in which the synergistic components are highly effective and useful.

While this invention has been described and exemplified in terms of its preferred embodiments, those skilled in the art will appreciate that variations and modifications may 'be made without departing from the spirit and scope of the present invention.

What is claimed is:

1. An antiseptic composition consisting essentially of soap and a synergistic combination of thiophene-Z-carboxy-4'-bromoanilide and 3,4,S-tribromosalicylanilide, said bromoanilide and said tribromosalicylanilide being contained in about equal amounts and in a total amount of from 0.1 to 5 percent based on the weight of the composition.

References Cited UNITED STATES PATENTS 3,240,71'0 3/1966 Schiltz 252'106 3,243,342 3/1966 Stecker 424-275 3,256,200 6/1966 Roller et al. 252106 3,276,955 10/ 1966 Casely et al 252-106 X LEON D. ROSDOL, Primary Examiner P. E. WILLIS, Assistant Examiner US. Cl. X.R. 

